Sortase mediated protein ubiquitination with defined chain length and topology.

Ubiquitination is a key post-translational modification on protein lysine sidechains known to impact protein stability, signal transduction cascades, protein-protein interactions, and beyond. Great strides have been made towards developing new methods to generate discrete chains of polyubiquitin and conjugate them onto proteins site-specifically, with methods ranging from chemical synthetic approaches, to enzymatic approaches and many in between. Previous work has demonstrated the utility of engineered variants of the bacterial transpeptidase enzyme sortase (SrtA) for conjugation of ubiquitin site-specifically onto target proteins.

Photochemical synthesis of an epigenetic focused tetrahydroquinoline library.

Discovery of epigenetic chemical probes is an important area of research with potential to deliver drugs for a multitude of diseases. However, commercially available libraries frequently used in drug discovery campaigns contain molecules that are focused on a narrow range of chemical space primarily driven by ease of synthesis and previously targeted enzyme classes (, kinases) resulting in low hit rates for epigenetic targets. Here we describe the design and synthesis of a compound collection that augments current screening collections by the inclusion of privileged isosteres for epigenetic targets.